Biology subjects

Leutgeb, S.

Publications and source records attributed to Leutgeb, S..

9 recordsLinked to original sources

bioRxiv2026

Working memory retention by medial entorhinal cortex low-dimensional neural dynamics

The ability to retain information over tens of seconds is essential for carrying out many routine tasks. Recurrently connected circuits are thought to support memory over these timescales, yet how they maintain and represent remembered information remains unclear. We asked whether the medial entorhinal cortex (mEC), where recurrent attractor dynamics generate grid-cell firing patterns and single toroidal attractor manifolds in two-dimensional environments, also supports low-dimensional neural activity patterns during memory retention. During a working-memory task, delay-period mEC dynamics did not show key features of grid firing in simple environments. Instead, broader mEC populations, not limited to grid cells, expressed multiple sequences and recurring activity patterns. Periodically repeating delay-period sequences retained task-relevant information, including past locations and future turn directions. These findings suggest that the mEC network generates low-dimensional dynamics more broadly, with grid-cell activity representing one manifestation and more complex manifold topologies supporting task-related representations during working memory.

neuroscience↗

bioRxiv2026

NPAS4 refines spatial and temporal firing in CA1 pyramidal neurons

NPAS4 is an activity-dependent transcription factor that, in CA1 of the hippocampus, regulates inhibitory synapses made onto the active pyramidal neuron. In principle, NPAS4 thereby allows the past activity of a neuron to influence how it encodes information, although this has not yet been demonstrated. Here, we generated a sparse, CA1-specific knockout (KO) of NPAS4 in the mouse hippocampus and used optogenetic tagging to identify KO neurons in vivo. Recordings from intermingled wild-type (WT) and KO neurons in awake behaving animals revealed that NPAS4 deletion degrades spatial representations and temporal precision of spiking: KO neurons exhibited larger place fields with reduced in-field firing and increased out-of-field firing, less stable place fields, reduced coupling to local field potential theta oscillations, and diminished phase precession. These findings demonstrate that NPAS4 plays a crucial role in refining the spatial and temporal properties of CA1 pyramidal neuron spikes, which themselves are thought to be fundamental building blocks of more complex processes such as learning and memory.

neuroscience↗

bioRxiv2025

Early impairment in dentate pattern separation in a rodent model of temporal lobe epilepsy.

The dentate gyrus of the hippocampal formation utilizes sparse neural coding to support memory formation. In temporal lobe epilepsy (TLE), the dentate undergoes extensive restructuring, including loss of local inhibition. It is unknown how circuit changes impact dentate network computations in awake behaving animals. Here we perform high-density tetrode recordings from the dentate in male rats treated with systemic kainic acid (KA) to induce TLE. In KA-treated rats, dentate spatial representations were less precise at the single neuron level, however the stability of the spatial code in representing repeated visits to the same location was retained at the population level. Despite spared spatial representation, the network computations for pattern separation were disrupted. The reorganized dentate network in KA-treated rats generated less distinct population activity patterns for different environments, specifically as a result of impaired rate-remapping. Changes in network computations paralleled impairments in a dentate-dependent memory task, potentially providing a link between altered pattern separation and behavioral discrimination. These deficits were present in animals with confirmed dentate circuit reorganization that had not yet developed spontaneous seizures - suggesting that the dentate network changes underlying altered rate-remapping and impaired dentate-dependent memory occur early in epileptogenesis.

neuroscience↗

bioRxiv2025

Mental exploration of future choices during immobility theta oscillations

Mental exploration enables flexible evaluation of potential future choices, guiding decision-making without requiring direct real-world iterations. Although the hippocampus is known to be active while imagining the future, the precise mechanisms that support mental exploration of future choices remain unclear. In the hippocampus, the theta rhythm (4-12 Hz) is prevalent during movement and supports memory coding during real-world exploration by organizing neuronal activity patterns into short virtual path segments (theta sequences) around the rats location. We observed these theta-related neural activity patterns during movement in a hippocampus-dependent working memory task and also, unexpectedly, theta oscillations and theta-related neural activity during immobility. Compared to standard theta sequences during movement, theta sequences during immobility differed in that they occurred at a shifted theta phase and preferentially represented remote locations, in particular the next choice in the working memory task. Coding for future locations was also observed during awake sharp wave ripple, but these short-lasting events occurred rarely and were biased toward frequently visited locations. Therefore, our findings suggest that recurring bouts of theta oscillations during immobility, which are also observed in primates and humans, support the cognitive demands of mental exploration in the hippocampal network and facilitate ongoing predictions of future choices.

neuroscience↗

bioRxiv2023

Low Rate Hippocampal Delay Period Activity Encodes Behavioral Experience

Remembering what just happened is a crucial prerequisite to form long-term memories but also for establishing and maintaining working memory. So far there is no general agreement about cortical mechanisms that support short-term memory. Using a classifier-based decoding approach, we report that hippocampal activity during few sparsely distributed brief time intervals contains information about the previous sensory motor experience of rodents. These intervals are characterized by only a small increase of firing rate of only a few neurons. These low-rate predictive patterns are present in both working memory and non-working memory tasks, in two rodent species, rats and Mongolian gerbils, are strongly reduced for rats with medial entorhinal cortex lesions, and depend on the familiarity of the sensory-motor context.

neuroscience↗

bioRxiv2022

Localized APP pathology in the hippocampus is sufficient to result in progressive disorganization of the timing of neuronal firing patterns

Deficits in spatial navigation are among the early symptoms in Alzheimers disease patients, consistent with the hippocampal formation as the site for spatial computations and disease onset. Although the correspondence between the early symptoms and brain regions that are affected early in the disease has been recognized, it is not clear whether progressive cognitive decline is solely caused by a spreading pathology or whether a focal pathology can by itself cause aberrant neuronal activity in a larger network. These possibilities cannot be distinguished in standard disease models which broadly express APP across brain regions. We therefore generated a mouse model in which the expression of mutant human APP was limited to hippocampal CA3 cells (CA3-APP mice). We first asked whether the limited pathology in CA3 can result in memory deficits and found impaired performance of CA3-APP mice in a hippocampus-dependent memory task. By then recording in the CA1 region, we asked to what extent neuronal activity patterns emerged in a brain region which received projections from APP-expressing CA3 cells, but did itself not show any primary pathology. While the spatial firing patterns of CA1 cells were preserved, we observed a reduced theta oscillation frequency in the local field potential and in a subpopulation of principal cells in CA1. Furthermore, CA1 interneurons showed decreased theta oscillation frequencies, and this effect was even more pronounced in CA3 interneurons, which also do not directly express APP. Pathology that is highly localized and limited to presynaptic cells is thus sufficient to cause aberrant firing patterns in postsynaptic neuronal networks, which indicates that disease progression is not only from a spreading molecular pathology but also mediated by progressive physiological dysfunction.

neuroscience↗

bioRxiv2022

Distinct roles of dentate gyrus and medial entorhinal cortex inputs for phase precession and temporal correlations in hippocampal CA3 place cells

The hippocampal CA3 subregion is a densely connected recurrent circuit that supports memory consolidation and retrieval by generating and storing sequential neuronal activity patterns that reflect recent experience. While theta phase precession is thought to be critical for generating sequential activity during memory encoding, the circuit mechanisms that support this computation across hippocampal subregions are unknown. By analyzing CA3 network activity in the absence of each of its theta modulated excitatory inputs, we show necessary and unique contributions of the dentate gyrus (DG) and the medial entorhinal cortex (MEC) to phase precession. DG inputs are essential for generating the preferential spiking of CA3 cells during late theta phases and for organizing the temporal order of neuronal firing, while MEC inputs modulate the general precision of phase precession. A computational model that accounts for the empirical findings suggests that DG inputs affect the phase and MEC inputs affect the amplitude of inhibitory subnetworks. Our results thus identify a novel and unique functional role of the DG for the generation of sequence coding in the CA3 recurrent circuit.

neuroscience↗

bioRxiv2021

Theta oscillations in the prefrontal-hippocampal circuit do not couple to respiration-related oscillations

Oscillatory activity is thought to coordinate neural computations across brain regions, and theta oscillations are critical for learning and memory. Because the frequency of respiratory-related oscillations (RROs) in rodents can overlap with the frequency of theta in the prefrontal cortex (PFC) and the hippocampus, we asked whether odor-cued working memory may be supported by coupling between these two oscillations. We first confirmed that RROs are propagated to the hippocampus and PFC and that RRO frequency overlaps with canonical theta frequency. However, we found low coherence between RROs and local theta oscillations in the hippocampus-PFC network when the two types of oscillations overlapped in frequency. This effect was observed during all behavioral phases including during movement and while odors were actively sampled when stationary. Despite the similarity in frequency, RROs and theta oscillations therefore appear to be limited to supporting computation in distinct networks, which suggests that sustained long-range coordination between oscillation patterns that depend on separate pacemakers is not necessary to support at least one type of working memory.

neuroscience↗

bioRxiv2020

Aβ-induced synaptic injury is mediated by presynaptic expression of amyloid precursor protein (APP) in hippocampal neurons

The patterns of A{beta}-induced synaptic injury were examined after targeting of the amyloid precursor protein (APP) preferentially to either CA1 or CA3 neurons using Cre-lox technology combined with tetracycline-regulated expression. Both CA1- and CA3-APP-expressing transgenic mouse lines exhibited reduction in long-term potentiation (LTP) only when APP was expressed in neurons presynaptic to the recording site, whereas LTP remained comparable to wild-type mice when APP was expressed in postsynaptic neurons. As quantified by both light and electron microscopy, this orientation-specific impairment in synaptic plasticity was mirrored by synaptic loss in regions receiving axonal inputs from neurons expressing APP. Furthermore, A(plaque deposition also occurred only in the postsynaptic axonal fields of APP-expressing neurons. These deficits were reversed not only with doxycycline to inhibit APP expression but also with {gamma}-secretase and Fyn kinase inhibitors, supporting the interpretation that the observed synaptic injury was mediated by A{beta}. Taken together, these results demonstrate that APP/A{beta}-induced synaptic toxicity is preferentially initiated by signaling of presynaptically expressed APP to the postsynaptic compartment.

neuroscience↗